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Vol. 60, Issue 1, 26-35, July 2001
The Biomedical Sciences Graduate Program (A.C.Z.) and the
Departments of Pharmacology (L.L.B., R.J.H., B.T., P.A.I.)
and Medicine (L.L.B., K.E.B., P.A.I.), University of California at San
Diego, La Jolla, California
The P2Y11 receptor is hypothesized to link to both
Gs and Gq, although this proposition is based
on expression and separate assays of Gs and Gq
function in different cell types [J Biol Chem 1997;272:31969-31973]. We have cloned and characterized a
canine P2Y11-like (cP2Y11)
receptor from cultured Madin Darby canine kidney (MDCK-D1) cells. When
cP2Y11 receptors are expressed in canine
thymocyte (CF2Th) cells that normally lack functional purinergic
responses, ADP
S stimulates phosphatidylinositol (PI) hydrolysis,
Ca2+ mobilization, and cAMP accumulation.
Pharmacologic analysis indicates that the stimulation of cAMP
production is direct and not a result of eicosanoid synthesis,
activation of PKC, or elevation of cell Ca2+. The
rank order of potency for stimulation of PI hydrolysis by cP2Y11 receptors (adenosine
5'-(2-O-thio) diphosphate = 2-methylthio-ADP 
2-methylthio-ATP 
ADP > ATP) differs from that of
hP2Y11 receptors. Microscopic examination of
MDCK-D1 cells expressing carboxyl-terminal green fluorescent protein
(GFP)-tagged cP2Y11
(cP2Y11-GFP) receptors indicates primarily
basolateral (BL) targeting. BL addition of 200 µM ADPS to
confluent monolayers of MDCK-D1 cells produces an increase in short
circuit current (Isc) (11.6 ± 1.6 µA/cm2) whereas apical addition of agonist has
no effect, confirming targeting of functional endogenous
P2Y11 receptors to the BL surface. In contrast,
when either cP2Y11 or
cP2Y11-GFP is overexpressed in MDCK-D1 cells, the
sensitivity of Isc to BL agonist increases by
nearly 2 orders of magnitude, as if receptor density normally limited
agonist potency; moreover, apical addition of ADPS now produces an
increase in Isc but with low potency. The data
support the BL localization of cP2Y11 receptors
and receptor coupling to changes in Isc in
MDCK-D1 cells except in cases in which receptors are overexpressed;
receptor overexpression leads to altered sensitivities and sites of
coupling to physiologic responses.
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